Abstracts

Rationale: Infantile spasms are age-specific epileptic seizures that manifest in infantile epileptic encephalopathies that usually have poor outcomes. Our lab has previously generated a chronic rat model of infantile spasms, the multiple-hit model, by using a combination of intracerebral injections of cytotoxic and pro-inflammatory compounds. As a result, the multiple-hit model demonstrates a chronic phenotype consisting of an early period with spasms, followed by appearance of other seizures and neurodevelopmental deficits. In this study, we investigate the role of the inflammatory cytokine interleukin 1beta in inducing spasms and the behavioral and cognitive delays seen in the multiple-hit model of spasms.Methods: Postnatal day 5 (PN5) male rats (n=5-6/group) were injected in the right motor cortex with 150, 30 or 0 ng of interleukin 1beta. The interleukin 1beta injected rats were video-recorded for one two-hour session on PN6 and PN7, then for two two-hour sessions on PN8-12 to count spasms. Weights and developmental motor reflexes (open field activity, surface righting time, negative geotaxis between PN5-20; horizontal bar between PN13-20) were assessed daily. Barnes maze was tested between PN16-19 to evaluate visuospatial learning and memory. Na ve age-matched male controls were also used to compare the neurodevelopmental milestones. The rats were perfused for histology at PN20.Results: All interleukin 1beta injected rats manifested spasms between PN6-10 (p<0.0001 compared to vehicle). Interleukin 1beta-injected rats manifested spasms from PN5 (mean spasms per hour +/- standard deviation: 4.8 +/- 2.2 for 150ng, 4.3 +/- 1.7 for 30ng) till PN11. We did not observe any significant (p<0.05) differences in spasms between the 150ng and 30ng dose. Vehicle-injected controls manifested only rare behaviors that resembled flexion spasms. Behavioral measures and weight gain were not affected by interleukin 1beta, and no mortality was seen.Conclusions: Interleukin 1beta injection causes epileptic spasms but no obvious behavioral deficits in pre-weaning rats. This suggests that epileptic spasms may not be sufficient to cause neurodevelopmental decline and that the etiology of epileptic spasms is an important factor in causing or predisposing to the associated comorbid behavioral and cognitive deficits.